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Manisit Das
As humans, we are naturally programmed to recognize patterns. They help us detect cues in our surroundings and aid our decision making. We associate camouflage patterns with battle dress, assortments of red and green with the holidays; these recognition events help us to put things in boxes in our head. This phenomenon is so natural that throughout evolution, our immune system has mastered the skill of spotting patterns as well.
Our body is crawling with microbes; some of them have the best of intentions in their heart (although I don’t think they have a heart in the most literal sense), while others do not. The innate immune system has to find ways to quickly recognize harmful pathogens, raise the alarm, and recruit battalions of immune cells to fight off the microbes. This whole process starts with the immune cells identifying evolutionarily conserved patterns on the pathogens, also known as pathogen-associated molecular patterns or PAMPs.
When PAMP-like components of the bacterial membrane or viral DNA or RNA are detected by proteins (called pattern recognition receptors or PRRs) on the immune cells, the innate immune system is activated. A robust immune response is launched; the immune cells slowly recognize the unique proteins on the attacking pathogens that are not evolutionarily conserved and initiate a targeted attack against these pathogens. This attacking mechanism of the immune response comes from adaptive immunity and is capable of developing memory against a previous pathogen. Thus, the innate immune response becomes broader and looks for generic patterns among pathogens, sometimes initiating rapid responses. The adaptive immune response is more specific but takes more time to develop, while the innate immune system holds the defense together.
At Oncobites, we have widely discussed how the immune system can be used to our advantage in anticancer therapy. Checkpoint inhibitor drugs, which disengage the brakes on the immune T cells and facilitate the targeting of the cancer cells, do not perform so well in solid tumors because of the immunosuppressive environment in such cancers. The cancer cells recruit suppressive immune cells; under normal conditions, suppressive immune cells prevent excessive inflammation and autoimmune disorders, but under the control of cancer cells, they are capable of sabotaging our immune system’s war on cancer. Researchers now believe that this is where PAMPs and PRRs come in. It is possible to deliver PAMPs to the tumor and trigger an immune response. This immune response is capable of modulating the immune environment in the tumor and providing a less extreme battleground for the checkpoint inhibitor drugs. Several drugs that are capable of activating the PRRs against advanced solid tumors are currently in the early stages of clinical trials.
While these successes make us hopeful about a brighter future for cancer immunotherapy and the battle against cancer, there are pitfalls associated with the innate immune system targets as well. Because innate immunity is generic, it is possible to overstimulate the immune system and trigger immune-related adverse events. Many of these therapeutics are thus delivered locally – i.e., within the tumor – in the clinic. However, this form of delivery limits the application of the therapy and demands surgical invasion. Furthermore, precisely tuning the drug distribution to limit systemic immune response is a challenge. Thus, many groups of pharmaceutical scientists, including my own, are exploring smart delivery systems for these drugs to locally modulate the immune microenvironment within the tumor while minimizing the systemic exposure of the drug and the associated side effects.
In a recent paper published in the journal Molecular Therapy, my colleagues and I used nanoparticles to deliver a dual functional RNA molecule that is capable of activating the innate immune system as well as triggering cancer cell death in pancreatic cancer. As we discussed in earlier posts, nanoparticles are tiny materials that can be engineered easily to fit the application, and they can be programmed to accumulate in certain tissue sites such as tumors, with minimal exposure to rest of the body.
We designed a nanoparticle system encapsulating a double-stranded RNA capable of activating a PRR called RIG-I. Our nanoparticle system was decorated with molecules targeting pancreatic tumors. The double-stranded RNA drug was also programmed to silence Bcl2, a gene that helps cancer cells to bypass cell death. Thus, the silencing of RIG-I triggered direct cancer cell killing and enhanced the therapy response coming from activating innate immunity. Overall, in mouse models of pancreatic cancer, we observed a strong antitumor response with a low dose of the drug. The delivery of the drug without nanoparticles showed no effect, suggesting that nanoparticle delivery can enhance the therapeutic effect of innate immune activator drugs like double-stranded RNAs, which are otherwise very unstable and easily cleared from the body before achieving its function. Nanoparticles can also improve the safety and ease of delivery by removing the need for local injections and allowing therapeutic effects at low doses with minimal systemic exposure. A company called Rigontech (which was recently acquired by Merck) is developing a cancer immunotherapy drug targeting the RIG-I pathway. They have a candidate drug called RGT100 that is currently undergoing clinical trials.
As early as the 1890s, Dr. William Coley observed that when bacterial toxins are introduced into tumors, they are capable of driving tumor regression. Researchers have since gained knowledge about the mechanisms of PAMPs and PRRs, and have studied the complex nature of our immune system. We are now more capable of fine-tuning the balances of the immune system and synergizing innate and adaptive immune systems to broaden our capability against cancers. The preclinical data coming from animal models are encouraging, and as these drugs move through to the advanced stages of the clinical pipeline, we will know whether innate immune targets are capable of warming up immunologically ‘cold’ tumors for checkpoint inhibitor drugs, thereby strengthening the foundation of cancer immunotherapy.
References:
Mullard, A. (2017). Can innate immune system targets turn up the heat on ‘cold’ tumours? Nature Reviews Drug Discovery, 17, 3.
Das, M., Shen, L., Liu, Q., Goodwin, T. J., & Huang, L. (2018). Nanoparticle Delivery of RIG-I Agonist Enables Effective and Safe Adjuvant Therapy in Pancreatic Cancer. Mol Ther.
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